Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000546.5(TP53):c.800G>A (p.Arg267Gln)

CA000424

127823 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: ca16e21b-853c-433e-88e5-601b2de6c525
Approved on: 2026-01-06
Published on: 2026-01-14

HGVS expressions

NM_000546.5:c.800G>A
NM_000546.5(TP53):c.800G>A (p.Arg267Gln)
NC_000017.11:g.7673820C>T
CM000679.2:g.7673820C>T
NC_000017.10:g.7577138C>T
CM000679.1:g.7577138C>T
NC_000017.9:g.7517863C>T
NG_017013.2:g.18731G>A
ENST00000503591.2:c.800G>A
ENST00000508793.6:c.800G>A
ENST00000509690.6:c.404G>A
ENST00000514944.6:c.521G>A
ENST00000604348.6:c.779G>A
ENST00000269305.9:c.800G>A
ENST00000269305.8:c.800G>A
ENST00000359597.8:c.800G>A
ENST00000413465.6:c.782+361G>A
ENST00000420246.6:c.800G>A
ENST00000445888.6:c.800G>A
ENST00000455263.6:c.800G>A
ENST00000504290.5:c.404G>A
ENST00000504937.5:c.404G>A
ENST00000509690.5:c.404G>A
ENST00000510385.5:c.404G>A
ENST00000610292.4:c.683G>A
ENST00000610538.4:c.683G>A
ENST00000610623.4:c.323G>A
ENST00000615910.4:c.767G>A
ENST00000617185.4:c.800G>A
ENST00000618944.4:c.323G>A
ENST00000619186.4:c.323G>A
ENST00000619485.4:c.683G>A
ENST00000620739.4:c.683G>A
ENST00000622645.4:c.683G>A
ENST00000635293.1:c.683G>A
NM_001126112.2:c.800G>A
NM_001126113.2:c.800G>A
NM_001126114.2:c.800G>A
NM_001126115.1:c.404G>A
NM_001126116.1:c.404G>A
NM_001126117.1:c.404G>A
NM_001126118.1:c.683G>A
NM_001276695.1:c.683G>A
NM_001276696.1:c.683G>A
NM_001276697.1:c.323G>A
NM_001276698.1:c.323G>A
NM_001276699.1:c.323G>A
NM_001276760.1:c.683G>A
NM_001276761.1:c.683G>A
NM_001276695.2:c.683G>A
NM_001276696.2:c.683G>A
NM_001276697.2:c.323G>A
NM_001276698.2:c.323G>A
NM_001276699.2:c.323G>A
NM_001276760.2:c.683G>A
NM_001276761.2:c.683G>A
NM_000546.6:c.800G>A
NM_001126112.3:c.800G>A
NM_001126113.3:c.800G>A
NM_001126114.3:c.800G>A
NM_001126115.2:c.404G>A
NM_001126116.2:c.404G>A
NM_001126117.2:c.404G>A
NM_001126118.2:c.683G>A
NM_001276695.3:c.683G>A
NM_001276696.3:c.683G>A
NM_001276697.3:c.323G>A
NM_001276698.3:c.323G>A
NM_001276699.3:c.323G>A
NM_001276760.3:c.683G>A
NM_001276761.3:c.683G>A
More

Likely Pathogenic

Met criteria codes 7
PP3 PM1_Supporting PM2_Supporting PP4_Moderate PS4_Moderate PS2_Moderate BS2_Supporting
Not Met criteria codes 9
PVS1 BS3 BS1 BP7 BP4 PM5 PS3 PS1 BA1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 2.4.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
The NM_000546.6: c.800G>A variant in TP53 is a missense variant predicted to cause substitution of Arginine by Glutamine at amino acid 267 (p.Arg267Gln). This variant has been identified as a de novo occurrence with confirmed parental relationships in one individual with a moderately LFS-associated cancer totaling 2 phenotype points (PS2_Moderate; Internal contributor). This variant has been reported in 5 unrelated families meeting Revised Chompret criteria. Based on this evidence, this variant scores 2.5 total points meeting the TP53 VCEP phenotype scoring criteria of 2-3.5 points. (PS4_Moderate; PMID: 25584008, Internal lab contributors). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributor). This variant has been observed in 2-3 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Supporting; Internal lab contributor). This variant has an allele frequency of 0.000004959 (8/1613260 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has a subpopulation allele frequency of <0.00004 in all non-bottleneck populations with 2 or more alleles present (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and retained growth suppression activity suggesting that this variant does not impact protein function; however, all assays did not agree (BS3_Supporting not met; PMIDs: 12826609, 30224644, 29979965, 39774325).This variant has 4 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (2-9 somatic occurrences, PMID: 30311369) (PM1_Supporting). Computational predictor scores (BayesDel = 0.5934; Align GVGD = Class C35) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS2_Moderate, PP4_Moderate, PS4_Moderate, BS2_Supporting, PP3, PM1_Supporting, PM2_Supporting. (Bayesian Points: 8; VCEP specifications version 2.4)
Met criteria codes
PP3
Computational predictor scores (BayesDel = 0.5934; Align GVGD = Class C35) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3).
PM1_Supporting
This variant has 4 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (2-9 somatic occurrences, PMID: 30311369) (PM1_Supporting).
PM2_Supporting
This variant has an allele frequency of 0.000004959 (8/1613260 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has a subpopulation allele frequency of <0.00004 in all non-bottleneck populations with 2 or more alleles present (PM2_Supporting).
PP4_Moderate
At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributor).
PS4_Moderate
This variant has been reported in 5 unrelated families meeting Revised Chompret criteria. Based on this evidence, this variant scores 2.5 total points meeting the TP53 VCEP phenotype scoring criteria of 2-3.5 points. (PS4_Moderate; PMID: 25584008, Internal lab contributors).
PS2_Moderate
This variant has been identified as a de novo occurrence with confirmed parental relationships in one individual with a moderately LFS-associated cancer totaling 2 phenotype points (PS2_Moderate; Internal contributor).
BS2_Supporting
This variant has been observed in 2-3 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Supporting; Internal lab contributor).
Not Met criteria codes
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and retained growth suppression activity suggesting that this variant does not impact protein function; however, all assays did not agree (BS3_Supporting not met; PMIDs: 12826609, 30224644, 29979965, 39774325).
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
4 different missense variants (c.800G>T, p.Arg267Leu; c.800G>C, p.Arg267Pro; c.799C>G, p.Arg267Gly; c.799C>T, p.Arg267Trp) in the same codon have been reported (ClinVar Variation IDs: 852206, 428867, 1761541, 141764). However, these variants do not meet criteria for PM5 code application (PM5 not met).
PS3
In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and retained growth suppression activity suggesting that this variant does not impact protein function; however, all assays did not agree (BS3_Supporting not met; PMIDs: 12826609, 30224644, 29979965, 39774325).
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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